P2Y2 receptors are present on body's mucosal surfaces, including the lungs, eyes, upper airways, mouth, vaginal tract and gastrointestinal tract, and on non-mucosal surfaces, such as the retinal pigment epithelium (RPE). The P2Y2 receptor coordinates the entire mechanism of mucociliary clearance in the upper portion of the lower respiratory and digestive tract. This process can be regulated therapeutically by local delivery of molecules that bind to and activate these receptors.
P2Y2 receptors are found on each of the three principal cell types that line the airways: ciliated epithelial cells, goblet cells, and Type II alveolar cells. Upon activation of the P2Y2 receptor on ciliated epithelial cells, salt and water are released from the cell, mucous secretions are hydrated, and ciliary beat frequency is increased. Activation of the P2Y2 receptor on goblet cells modulates the release of mucin. And when the P2Y2 receptors on Type II alveolar cells are activated, surfactant is released, maintaining the surface tension of the smallest peripheral airways and preventing their collapse.
Activation of mucosal hydration and mucociliary clearance in the lungs and upper airways via P2Y2 modulators provides opportunities for treating diseases like cystic fibrosis and upper respiratory disorders involving nasal symptoms like congestion, pressure and nasal blockage. These upper respiratory disorders include rhinosinusitis, allergic rhinitis, and upper respiratory infections like the common cold and influenza. Also, increasing mucociliary clearance in the lungs allows for non-invasive collection of mucus samples from the lungs, which may be beneficial in the diagnosis of lung cancer.
Chronic obstructive pulmonary disease (COPD) is characterized by mucus secretion retention in the lungs, resulting in progressive lung dysfunction over time. Many patients diagnosed with COPD have a disorder called chronic bronchitis (CB). Cystic fibrosis and Primary Ciliary Dyskinesia (PCD) are other examples of lung disorders that have a clinical profile similar to COPD. Primary or secondary ciliary dyskinesia results in retained secretions that can only be cleared by coughing. Most patients with COPD utilize coughing to help clear retained secretions because of impaired mucociliary clearance.
Sinusitis, also characterized by an accumulation of retained mucous secretions, is an inflammation of the paranasal sinuses typically associated with an upper respiratory infection. This condition affects many people in the US.
Otitis media (OM) is a viral or bacterial infection of the middle ear, primarily afflicting children under the age of three. It is usually precipitated by an upper respiratory infection that spreads into the middle ear via the nasopharynx and eustachian tube. Following antibiotic treatment, accumulated fluid in the middle ear causes hearing impairment and potential language and cognitive development delays. Improved clearing of middle ear secretions would reduce or eliminate significant sequelae of otitis media.
Pneumonia is an illness of the respiratory system that is linked to retained secretions. This illness afflicts many people each year and is a leading cause of death for chronically ill patients. Amongst those at risk for developing pneumonia, patients that are immobilized generally have a high risk of developing the illness.
At times, it is therapeutically desirable to increase drainage of the lacrimal system because improper functioning of the lacrimal drainage system can result in excessive tearing (epiphora), mucopurulent discharge, and/or recurrent dacryocystitis. Current treatments for nasolacrimal duct obstruction are mostly invasive surgical procedures, which are not desirable. Tear secretion can be stimulated from lacrimal accessory tissues via P2Y2 and/or P2Y4 purinergic receptor-mediated mechanisms similar to those which hydrate airway epithelia. Dry eye disease is the general term for indications produced by abnormalities of the precomeal tear film characterized by a decrease in tear production or an increase in tear film evaporation, together with the ocular surface disease that results. The current pharmaceutical treatment of dry eye disease is often limited to administration of artificial tears (saline solution) to temporarily rehydrate the eyes. This treatment generally provides only short-term relief, and frequent dosing is necessary.
Normally, mucous secretions are removed via the mucociliary clearance (MCC) system. MCC relies on the integrated action of three components: 1) mucus secretion by goblet cells and submucosal glands; 2) the movement of cilia on epithelial cells which propels the mucus across the luminal surface; and 3) ion transport into and out of luminal epithelial cells which concomitantly controls the flow of water into the mucus. Secretory functions of the uterine, cervical and vaginal mucous cells also have a profound impact on the function and health of the reproductive tract. For example, the quality and quantity of cervical mucus changes throughout the menstrual cycle and such changes dramatically influence fertility. Under the influence of rising estrogen levels, cervical mucus becomes thin, allowing the passage of spermatozoa. Later in the menstrual cycle, as progesterone levels increase, mucus becomes thick and hostile to sperm penetration, thereby closing the window of fertility. Such thickening of cervical mucus is thought to be one of the primary modes of contraceptive action for progestin-only contraceptives.
Estrogen stimulates the production of thin, isotonic mucus, with increased amounts of high molecular weight glycoproteins. Cervical mucus contains 98% water at mid cycle and 90% at other times. Cervical mucus is also rich in metallic ions, enzymes (such as alkaline phosphatase, etc.), soluble proteins, and salts. The gel phase of cervical mucus contains high molecular weight glycoproteins called mucin. Mucin micelles cross-link by disulfide bridges. Estrogen and progesterone control the arrangement of these micelles.
Postmenopausal women often experience atrophic vaginitis or vaginal dryness. During vaginal atrophy, the vaginal epithelium decreases in thickness, hydration, ruggae (folds), and blood flow. Causes of atrophic vaginitis include a decrease in the amount of estrogen present both locally and systemically as well as environmental factors such as chemotherapy, antihistamines, smoking cigarettes, excessive exercise, and vaginal products (i.e. douches, deodorants, and perfumes).
Estrogens or hormone replacement therapies can be effective in reducing vaginal dryness, but possible dangerous side effects include higher incidences of breast cancer, endometrial cancer, blood clots, nausea, breast tenderness, and headache. Products that are available over-the-counter include lubricants as moisturizers. These products are mostly water, provide only temporary relief for symptoms, and have virtually no long-term benefits to the vaginal tissue.
Accordingly, the need exists for compounds that act at P2Y receptors, e.g., P2Y1 or P2Y2 receptor, and thereby provide a therapeutic benefit by increasing mucus secretion from mucosal surfaces.